The facile manipulation of reactive functionality is a key factor in the development of efficient, high-yielding methods for combinatorial syntheses. For example, activated carboxylic acid derivatives have served as reactive building blocks in the solid-phase preparation of a wide variety of oligomeric and small molecule libraries. In most cases, the solid-phase protocol allows reactions on a polymer-bound scaffold to be driven to completion by making use of large excesses of reagents in solution that can be easily filtered away from the polymer support. After the scaffold has been modified, an additional cleavage step then frees the small molecule from the polymer support into solution for isolation. An alternative approach is to support a reagent or catalyst that can be used in excess to induce a chemical transformation on other reagents in solution, and once again, simple filtration can serve as a means for product separation and isolation.
Isocyanates are well known in the art to be useful intermediates in the production of pharmaceuticals and agrochemicals. A typical preparation of isocyanates involves the phosgenation of primary amines. Phosgene is a very reactive reagent, and many compounds have functional groups in addition to the primary amine which would also be react with phosgene. Therefore, many highly functionalized compounds cannot be prepared from the amine as the starting point via the isocyanate as an intermediate. Similarly, unsymmetrical ureas with different groups on each of the nitrogen atoms adjacent to the carbonyl, are also difficult to directly synthesize without the use of laboriously prepared protecting groups. A need exists to develop simple syntheses to overcome these problems.
The reaction of oximes with phosgene in solution phase to produce oxime-derived chloroformates is known in the art. Itoh et al. (Organic Syntheses, 59, 1975, 95-101 and Bull. of the Chem. Soc. of Japan, 50, 1977, 718-721) have used the reaction of various oximes with phosgene as part of a scheme to prepare a t-butoxycarbonylating reagent, which is used in peptide synthesis. The chloroformate that is formed is in the solution phase and is never isolated, but rather is used in situ. The use of the chloroformates in syntheses has the disadvantage that it must be stored and used under an inert atmosphere since they are very reactive and decompose in open air liberating HCl.
DeGrado and Kaiser (J. Org. Chem. 1980, 45, 1295-1300 and J. Org. Chem. 1982, 47, 3258-3261) have used an oxime resin as a solid phase reagent for peptide synthesis. A C-terminal amino acid is anchored onto the oxime resin as its oxime-derived ester, allowing further amino acids to be added stepwise by standard peptide coupling. Once the desired peptide is assembled, it is cleaved from the oxime resin by treatment with nucleophile such as hydrazine to afford the peptide hydrazide.
A functionalized polymer to serve as a vehicle to deliver reactive functionality, such as an isocyanate, into the solution phase, would be highly useful in the development of combinatorial syntheses for ureas, carbamates, sulfonylureas, hydantoins and other heterocyclic systems of biological importance. High yields, high recovery with few or no undesired side reactions, stability, and a suitability for automation are requirements to satisfy the need in the field.